TITLE: Giant Axonal Neuropathy Gene Therapy ABSTRACT Giant Axonal Neuropathy (GAN, OMIM #256850) is a rare chronic neurodegenerative disease characterized by enlarged axons with disordered microtubules and intermediate filaments (IFs), which is fatal by the third decade of life. The disease pathology is due to homozygous loss-of- function mutations in the GAN gene, which encodes the protein gigaxonin. The underlying pathology is due to the disorganization and accumulation of IFs, including vimentin, alpha- internexin, neurofilaments, peripherin, and GFAP. GAN patients have normal cognitive function, and the most severe (and fatal) symptoms of GAN are the result of dysfunction and death of motor and sensory neurons in the spinal cord and DRG. The phenotypic contribution of IF dysfunction in other tissues such as the brain, autonomic nerves, and peripheral organs is poorly understood. Since 2008 we have been developing a gene transfer approach to treat GAN using intrathecal delivery of AAV9/GAN vectors, funded entirely by a small non-profit foundation called Hannah's Hope Fund. This effort culminated in a preIND (investigational new drug) meeting with the FDA in January 2012, and a RAC meeting for a proposed clinical trial in June 2013. Submission of an IND for a Phase I safety GAN gene therapy clinical trial is expected in summer of 2013, focused on rescuing spinal cord motor and sensory neurons. Sponsored by Hannah's Hope Fund, this trial will occur at the NIH Clinical Center under the direction of Dr. Carsten Bonnemann. This Phase I trial is aimed at establishing the safety of our general gigaxonin gene transfer approach in older patients that are eager to participate and otherwise untreatable. This patient population is made up of individuals that will be dead or too far progressed in their disease to participate in a later trial. While the Phase I trial is underway, this proposal aims to better characterize GAN in ways that could inform a Phase II/III trial and also identify new therapeutic targets if our approach needs to be modified. Further, it aims to optimize the gene transfer approach and develop a GAN knock-out rat.